Cannabinoids and Glaucoma I Tomida, R G Pertwee, a Azuara-Blanco

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Br J Ophthalmol 2004;88:708–713. doi: 10.1136/bjo.2003.032250 Glaucoma is one of the leading causes of blindness in the without medical supervision. Recently, several states have legalised the medical use of canna- world. In spite of the diverse therapeutic possibilities, new binoids. In the United Kingdom, cannabis is and better treatments for glaucoma are highly desirable. registered as a schedule I—class C drug.1–4 The Cannabinoids effectively lower the intraocular pressure medical use of cannabinoids is currently restricted to dronabinol (Marinol, synthetic D9- (IOP) and have neuroprotective actions. Thus, they could tetrahydrocannabinol) and nabilone; these drugs potentially be useful in the treatment of glaucoma. The are administered orally as anti-emetics and purpose of this article is to provide the reader with an appetite stimulants for patients with AIDS or on chemotherapy. Other potential clinical appli- overview of the latest achievements in research into the cations for cannabinoids, including glaucoma potential use of cannabinoids for glaucoma. therapy, are currently under intense investiga- ...... tion (see below).

annabis/marijuana is the most frequent PHARMACOLOGY illicit drug used today for recreational The cannabis plant has more than 480 chemical 5 Cpurposes. Yet it is not widely known that constituents. Of these, there is a group of at least the cannabis plant (Cannabis sativa; Latin for 66 compounds that contain only carbon, hydro- ‘‘planted hemp’’) (fig 1) is one of the oldest gen, and oxygen and are known collectively as drugs used for medical purposes. Its therapeutic cannabinoids. The remaining constituents of use was first recorded in a classical medicine cannabis include nitrogenous compounds such book by the Chinese emperor Shen Nung in 2737 as amino acids, proteins and glycoproteins, sugars, hydrocarbons, alcohols, aldehydes, BC. The medical use of cannabis was also known in other ancient cultures throughout India, ketones, simple acids, fatty acids, esters and lactones, steroids, terpenes, non-cannabinoid Assyria, Greece, Africa, South America, Egypt, phenols, flavonoids, pigments (carotene and and the Roman Empire.1 zanthophylls), and vitamin K. Terpenes are Cannabis was introduced on a larger scale into thought to be responsible for the characteristic Western medicine during the 19th century, odour of cannabis plants (fig 1). The main primarily by British doctors. They accumulated http://bjo.bmj.com/ psychoactive constituent of cannabis is the experience in the use of ‘‘Indian hemp’’ while cannabinoid, D9-tetrahydrocannabinol (D9- working in the colonies, recommending it as an THC), the structure of which was determined appetite stimulant, analgesic, muscle relaxant, by Gaoni and Mechoulam in the 1960s (fig 2).5 anticonvulsant, and hypnotic. In 1839, Dr Most research into the pharmacological proper- William Brooke O’Shaughnessy, an Irish physi- ties of plant cannabinoids has focused on this cian at the Medical College of Calcutta, published cannabinoid and, indeed, with the exception of a detailed report ‘‘On the preparations of the cannabinol and cannabidiol (figs 2 and 3), other on September 26, 2021 by guest. Protected copyright. Indian Hemp or Gunjah.’’ After performing plant cannabinoids have been subjected to little animal studies, he determined that cannabis or no pharmacological research.67 preparations were safe and effective in treating It is now generally accepted that D9-THC rabies, rheumatism, epilepsy, and tetanus. The produces many of its effects by acting through Ohio Medical Society of Physicians reported in cannabinoid receptors of which there are at least 1860 successful treatment of ‘‘stomach pain and 8 two subtypes, CB1 and CB2. Both subtypes are gastric distress,’’ psychosis, chronic cough, coupled through Gi/o proteins, negatively to gonorrhoea, and neuralgia with cannabis. The adenylate cyclase and positively to mitogen plant was difficult to store, its extracts were activated protein kinase. In addition, CB1 recep- variable in potency, and the effects of oral tors are positively or negatively coupled through ingestion were not constant. Other new drugs Gi/o proteins to certain calcium and potassium See end of article for were becoming available in the early 1900s with authors’ affiliations channels. CB1 receptors, which were cloned in ...... more reliable effects, and cannabis began to be 1990, are present in brain, spinal cord, and misused for recreational purposes. The American certain peripheral tissues that include lung, Correspondence to: Marijuana Tax Act of 1937 intended to prevent heart, urogenital and gastrointestinal tracts, A Azuara-Blanco, PhD, 9–11 FRCS(Ed), The Eye Clinic, non-medical use, but made cannabis difficult to and the eye. Many CB1 receptors are present Aberdeen Royal Infirmary, obtain for medical purposes too, and it was on central and peripheral neurons, one of their Aberdeen AB25 2ZN, UK; subsequently removed from the US pharmaco- functions being the modulation of neurotrans- [email protected] poeia in 1942. mitter release. CB2 receptors, cloned in 1993, Accepted for publication In the United States cannabis is now classified seem to be located especially in cells and tissues 4 October 2003 as a schedule I drug, regarded as having high associated with the immune system, such as ...... potential for abuse, and to be unsafe to take the tonsils, spleen, and different types of

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retrograde synaptic messengers.12 Following their release, the Br J Ophthalmol: first published as 10.1136/bjo.2003.032250 on 16 April 2004. Downloaded from effects of at least some endocannabinoids are thought to be rapidly terminated by cellular uptake and intracellular enzymatic hydrolysis.13 As detailed elsewhere68 some established cannabinoid receptor agonists bind more or less equally well to CB1 and CB2 receptors, important examples being WIN55212-2, which 9 has marginally greater CB2 than CB1 affinity, and D -THC, HU-210, CP55940, and nabilone (fig 3). As to CB1 selective agonists other than noladin, these include the anandamide analogues, methanandamide, O-1812, arachidonyl-29-chloro- ethylamide (ACEA), and arachidonylcyclopropylamide (ACPA). Examples of CB2 selective agonists are the THC Figure 1 Photograph of the Cannabis sativa plant (provided by GW analogues, L-759633, L-759656, JWH-133 and HU-308. Pharmaceuticals, Wiltshire, UK) Selective CB1 and CB2 receptor antagonists have also been developed, the most important of these being the CB1 leucocytes.89 One role of these receptors is modulation of selective SR141716A, AM251, AM281 and LY320135, and 8 cytokine release. the CB2 selective SR144528 and AM630. There is evidence, Endogenous agonists for cannabinoid receptors have also however, that these compounds are not ‘‘silent’’ antago- 14 been discovered; this system of ‘‘endocannabinoids’’ and nists. Thus, as well as attenuating the effects of CB1 or CB2 receptors constituting what is now generally known as the receptor agonists, they can by themselves elicit responses in endocannabinoid system.12 The endocannabinoids that have some cannabinoid receptor-containing tissues that are been indentified to date are all analogues of arachidonic acid. opposite in direction from those elicited by CB1 or CB2 They include arachidonoyl ethanolamide (anandamide; receptor agonists. While some of these ‘‘inverse cannabimi- AEA), 2-arachidonoyl glycerol (2-AG) which bind more or metic effects’’ may be attributable to a direct antagonism of less equally well to CB1 and CB2 receptors, and 2-arachidonyl responses elicited at cannabinoid receptors by released glyceryl ether (noladin) which is CB1 selective (fig 4). AEA endocannabinoids, there is evidence that this is not the only behaves as a partial cannabinoid receptor agonist with less possible mechanism and that these compounds are in fact all CB than CB efficacy. Within the nervous system, endocan- 2 1 inverse agonists that can reduce CB1 or CB2 receptor nabinoids are synthesised and released by neurons on constitutive activity. demand, functioning as neurotransmitters or neuromodula- tors. There is also evidence that endocannabinoids serve as http://bjo.bmj.com/ on September 26, 2021 by guest. Protected copyright.

Figure 2 Chemical structure of typical classic cannabinoids D9- Figure 3 Chemical structure of nabilone, cannabidiol, and tetrahydrocannabinol, cannabinol, and HU-211. cannabigerol.

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dysphoria, disruption of short term memory, cognitive Br J Ophthalmol: first published as 10.1136/bjo.2003.032250 on 16 April 2004. Downloaded from O impairments, sense of time distortion, reduced coordination, OH and sleepiness.4 N An earlier report on the effect of smoked marijuana H indicated the possibility of tolerance. Thus, the IOP reduction appeared to be inversely related to the duration of marijuana Anandamide use.30 In contrast, Dawson et al31 reported on their ophthal- (AEA) mological findings comparing non-users with long term users of marijuana (10 years or more). After applying the water loading test to both groups, the reduction of IOP associated O with marijuana treatment was similar between users and OH non-users. O Since these early observations numerous studies have been conducted confirming that different cannabinoids, including OH cannabidiol, cannabigerol, endogenous cannabinoids, and some synthetic cannabinoids, can reduce the IOP when 2-Arachidonoyl administered systemically and topically (see below). glycerol Obviously, smoking of marijuana is not advisable as a long (2-AG) term treatment. In addition to the acute side effects, long term marijuana smoking is associated with emphysema-like lung changes, and possible increase in the frequency of lung OH cancer.32 Oral administration has been evaluated. However, O there is a poor and variable absorption with this route,33 at OH least for the cannabinoid formulations that have been investigated so far. 2-Arachidonyl glycerol ether Mechanism of IOP reduction (noladin) The mechanism of action of cannabinoids in the human eye is not fully understood. Until recently, the effect of Figure 4 Chemical structure of endogenous cannabinoids anandamide cannabinoids on IOP was assumed to be mediated through (AEA), 2-arachidonoyl glycerol (2-AG), and 2-arachidonyl glyceryl the CNS. Studies involving unilateral topical application of ether (noladin). cannabinoids34 35 showed a large difference between the treated and untreated eye, suggesting a localised action. The AEA activates vanilloid (TRPV1) receptors in addition to experiments of Liu et al36 revealed evidence pointing in the 9 CB1 and CB2 receptors and there is also growing evidence for same direction: bolus administration of D -THC into the the existence of non-CB1, non-CB2, non-vanilloid pharma- cerebral ventricles, as well as ventriculocisternal perfusion cological targets for AEA and/or other cannabinoids.815There with D9-THC in rabbits, in contrast with intravenous is evidence too that classic cannabinoids such as D9-THC, administration, did not change the IOP. Thus, the main site HU-211, and CBD have antioxidant properties (see of action of cannabinoids on IOP is not in the central nervous below).7 16–18 In addition, D9-THC can act through presynaptic system. http://bjo.bmj.com/ CB1 receptors in the CNS to inhibit glutamic acid release and Pharmacological and histological studies support the direct 818 that HU-211 can block glutamate (NMDA) receptors. role of ocular CB1 receptors in the IOP reduction induced by 11 As well as showing therapeutic potential as neuroprotec- cannabinoids. Straiker et al detected CB1 receptors in ocular tive agents, D9-THC and CBD have other potential clinical tissues of the human eye, including the ciliary epithelium, applications, as indeed does the CB1 receptor antagonist/ the trabecular meshwork, Schlemm’s canal, ciliary muscle, inverse agonist, SR141716A.7 18–20 D9-THC, for example, is ciliary body vessels, and retina. Porcella et al10 found high already used in the clinic as an appetite stimulant and anti- levels of CB1 mRNA in the ciliary body. The anatomical on September 26, 2021 by guest. Protected copyright. emetic.18 In addition, this cannabinoid will most likely prove distribution of cannabinoid receptors suggests a possible to be useful as an anti cancer drug21 and for the management influence of endogenous cannabinoids on trabecular and of pain,22 23 and of various kinds of motor dysfunction that uveoscleral aqueous humour outflow and on aqueous include the muscle spasticity, spasm, or tremor associated humour production. In addition to the proved IOP lowering 24 37 with multiple sclerosis and spinal cord injury, the tics and effect of CB1 receptor agonists, Pate et al could antagonise psychiatric signs and symptoms of Tourette’s syndrome, and the IOP lowering effect of CP-55,940 (a synthetic CB1 the dyskinesia that is produced by L-dopa in patients with agonist) by pretreating the animals with SR 141716A (a 25–27 38 Parkinson’s disease. As now discussed, one other impor- CB1 receptor antagonist). Similarly, Song et al found that tant potential clinical application for cannabinoids, is the the IOP lowering effect of topical WIN-55,212-2 was management of glaucoma. significantly reduced by topically administered SR141716A. Using the synthetic cannabinoid WIN-55,212-2, Chien et CANNABINOIDS AND GLAUCOMA al39 could demonstrate an 18% reduction in the aqueous In 1971, Hepler and Frank reported a 25–30% IOP lowering humour production in monkeys but without significant effect of smoking marijuana in a small number of subjects.28 change in the trabecular outflow facility. As this percentage The duration of action of marijuana after smoking was appeared not sufficient to account for the total IOP lowering relatively short, about 3–4 hours, and there seemed to be a effect, other additional mechanisms were thought to be dose-response relation.28 29 Other ocular effects were observed involved. such as conjunctival hyperaemia, reduced tear production, The IOP reducing effect does not seem to be related to a and change in pupil size.29 Acute systemic side effects systemic reduction of arterial blood pressure.40 However, a induced by marijuana smoking included reduction of direct effect on the ciliary processes, and specifically a systemic blood pressure and tachycardia.4 Psychotropic reduction in capillary pressure, leading to changes in aqueous effects were very variable and included euphoria or humour dynamics, has been proposed.41 Green et al42 showed

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that D9-THC decreased the secretion of ciliary processes and rat optic nerve (optic nerve axotomy), showed a beneficial Br J Ophthalmol: first published as 10.1136/bjo.2003.032250 on 16 April 2004. Downloaded from led to a dilatation of the ocular blood vessels through a effect of HU-211 on injury induced metabolic and electro- possible b adrenergic action. In addition, Sugrue43 indicated physiological deficits.63 However, the optic nerve crush model that cannabinoids may inhibit calcium influx through may not resemble the mechanisms responsible for glauco- presynaptic channels and in this way reduce the noradrena- matous nerve damage. line release in the ciliary body, leading to a decrease in the Classic cannabinoids such as D9-THC, HU-211, and CBD 10 production of aqueous humour. Porcella et al proposed that have antioxidant properties that are not mediated by the CB1 cannabinoids might be acting as vasodilators on blood vessels receptor. As a result, they can prevent neuronal death by of the anterior uvea, thus improving the aqueous humour scavenging toxic reactive oxygen species produced by over- uveoscleral outflow. stimulation of receptors for the excitatory neurotransmitter, Green et al44 45 postulated that some cannabinoids may glutamic acid.7 16–18 64 influence the IOP through a prostaglandin mediated Cannabinoids have vasorelaxant properties and so might mechanism. For example, topically applied AEA is hydrolysed be able to increase the ocular blood flow. The mediator to arachidonic acid, which is a COX pathway precursor of endothelin-1, produced by vascular endothelial cells, has a prostaglandins.46 47 significant role in the regulation of local circulation, The topical application of the CB2 receptor agonist JWH- producing vasoconstriction and being involved in the 133 used in in vivo experiments by Laine et al48 did not have pathophysiological processes of ischaemic and haemorrhagic any effect on IOP compared to vehicle treatments, indicating stroke, Raynaud’s phenomenon, ischaemic heart disease and 65 that CB2 receptor agonists may not be involved in the pulmonary arterial hypertension, among others. The possi- regulation of IOP. ble role of endothelin-1 in the pathogenesis of glaucoma has been suggested. For example, patients with open angle Topical application of cannabinoids glaucoma may have an abnormal increase in plasma To minimise possible systemic adverse side effects and endothelin-1 in response to vasospastic stimuli.66 67 maximise the dose at the site of action, topical application Mechoulam et al61 could demonstrate that 2-arachidonoylgly- would be the ideal form of administration. However, natural cerol, an endogenous cannabinoid, was able to reduce cannabinoid extracts as well as synthetic forms are highly endothelin induced Ca2+ mobilisation, inhibiting vasocon- lipophilic and have low aqueous solubility, creating practical striction. Thus, cannabinoids may have beneficial properties difficulties for this mode of administration. in ischaemia induced optic nerve damage. After instillation of an eye drop of any medication, loss of the instilled solution via the lacrimal drainage system and FUTURE DIRECTIONS poor drug penetration results in only ,5% of an applied dose Cannabinoids have the potential of becoming a useful reaching the intraocular tissues. The cornea is usually the treatment for glaucoma, as they seem to have neuroprotective major pathway for intraocular penetration of topical medica- properties and effectively reduce intraocular pressure. tions. The corneal epithelium is highly lipophilic and its However, several challenges need to be overcome, including penetration is a rate limiting step for lipophilic drugs. the problems associated with unwanted systemic side effects Aqueous solubility is another drug property important for (psychotropic, reduction in systemic blood pressure), possible efficacy of delivery, as the surface of the eye is constantly tolerance, and the difficulty in formulating a stable and moistened by tear fluid. Additional factors affecting corneal effective topical preparation. Some cannabinoids such as HU- absorption include the molecular size, charge, and degree of 49 211 and cannabidiol do not have psycotropic effects, while ionisation. maintaining their IOP lowering action, so that further http://bjo.bmj.com/ Previous experiments with topical cannabinoid solutions research on these compounds would be desirable. Tolerance involved the use of light mineral oil as a vehicle, but proved 30 50 51 may develop after repeated use of cannabinoids. However, to be irritant to the human eye. Recently, different tolerance might be beneficial if it develops only or preferen- microemulsions and cyclodextrins (macrocyclic oligosacchar- tially to unwanted side effects. There has been recent ides) have been shown to improve the corneal penetration of progress in the use of microemulsions and cyclodextrins to cannabinoids. These formulations successfully induced an overcome the barriers in ocular penetration of topically unilateral IOP lowering effect.52–58 Cyclodextrins have already 56 applied cannabinoids. on September 26, 2021 by guest. Protected copyright. been used efficiently by Porcella et al to administer the Other possible applications of cannabinoids in ophthal- synthetic cannabinoid WIN-55,212-2 topically to glaucoma mology could be explored. Age related macular degeneration patients. (AMD) is the leading cause of blindness in the United Neuroprotective and vascular actions of cannabinoids Kingdom. Perhaps the potent antioxidant properties of the cannabinoids may be beneficial in AMD, offering a possible In glaucoma, the final pathway leading to visual loss is the 68 selective death of retinal ganglion cells through apoptosis. alternative to established antioxidant supplements. Apoptosis is initiated by axonal injury at the optic disc, either Cannabinoids have been shown to inhibit angiogenesis, leading to a decrease in the expression of proangiogenic by compression and/or by ischaemia. In ischaemia, glutamate 69 is released and activates NMDA receptors. NMDA receptor factors such as VEGF. Evidence suggests that VEGF plays a activation appears to be one of several pathways that result in major part in the development of choroidal neovascularisa- tion in AMD, and clinical trials using anti-VEGF therapies are apoptotic cell death. After activation of NMDA receptors 70 being conducted. The CB2 receptors are also under intense there is an influx of calcium into the cells and free radicals 71 are generated. Substances that prevent this cascade of events investigation for their possible immunomodulatory effects. and inhibit the retinal ganglion cell death are currently under The anti-inflammatory properties of CB2 receptor agonists investigation.59 might also prove to be of therapeutic relevance in different Recent studies have documented the neuroprotective forms of inflammatory eye disease. 9 properties of cannabinoids. There is evidence that D -THC ...... can inhibit glutamic acid release by increasing K+ and 2+ Authors’ affiliations decreasing Ca permeability and that the synthetic canna- I Tomida, A Azuara-Blanco, Department of Ophthalmology, Aberdeen binoid HU-211 can block glutamate (NMDA) recep- Royal Infirmary, University of Aberdeen, UK 8 9 18 59–62 tors. These actions are mediated by presynaptic CB1 R G Pertwee, Department of Biomedical Sciences, Institute of Medical receptors. Yoles et al, using a calibrated crush injury to adult Sciences, University of Aberdeen, UK

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